Design, Synthesis, and Structural Optimization of Lycorine-Derived Phenanthridine Derivatives as Wnt/β-Catenin Signaling Pathway Agonists

Lycorine is a benzylphenethylamine-type alkaloid member of the Amaryllidaceae family. A lycorine derivative, HLY78, was previously identified as a new Wnt/beta-catenin signaling pathway agonist that targets the DAX domain of axin. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships of lycorine-derived phenanthridine derivatives as agonists of the Wnt/beta-catenin signaling pathway are presented. This research suggests that triazole groups are important pharmacophores for Wnt activation; triazole groups at C-8 and C-9 of phenanthridine compounds markedly enhanced Wnt activation. A C-11-C-12 single bond is also important for Wnt activation. On the basis of these findings, two Wnt agonists were designed and synthesized. The results for these agonists indicated that the combination of a 4-ethyldihydrophenanthridine skeleton and a triazole substituent improves Wnt activation. These compounds may be useful in further pharmacological or biological studies.